In the past, iontophoresis has been defined to be "the introduction, by means of electric current, of ions of soluble salts into the tissues of the body for therapeutic purposes." Iontophoretic devices have been used since the early part of this century for delivering agents in ionized form.
The iontophoresis process has been found to be useful in the transdermal administration of drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, and many other drugs. Perhaps the most common use of iontophoresis is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically. The pilocarpine stimulates sweat production; the sweat is collected and analyzed for its chloride content to detect the presence of the disease.
Presently known iontophoretic devices use at least two electrodes, positioned in intimate contact with some portion of the skin of the body. A first electrode, called the active or donor electrode, delivers the ionic substance, medicament, drug precursor or drug into the body by iontophoresis. The second electrode, called the counter or return electrode, closes an electrical circuit including the body, the first electrode and a source of electrical energy, such as a battery. For example, if the ionic substance to be driven into the body is positively charged, the anode will be the active electrode and the cathode will serve as the counter electrode to complete the circuit. If the ionic substance to be delivered is negatively charged, the cathode will be the active electrode and the anode will be the counter electrode.
Alternatively, both the anode and cathode may be used to deliver drugs of opposite electrical charge into the body. In this situation, both electrodes are considered to be active or donor electrodes. For example, the anode can drive a positively charged ionic substance into the body, and the cathode can drive a negatively charged ionic substance into the body.
More recently, it has been determined that iontophoretic delivery devices can also be used to deliver an uncharged drug or agent into the body. This is accomplished by a process known as electroosmosis. Electroosmosis is the transdermal flux of a liquid solvent (e.g., the liquid solvent containing the uncharged drug or agent) that is induced by the presence of an electrical field imposed across the skin by the donor electrode. As used herein, the terms "iontophoresis" and "iontophoretic" refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by electroosmosis, (3) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (4) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.
The terms "drug" and "beneficial agent" are used interchangeably and are intended to have their broadest interpretation, namely any therapeutically active substance that is delivered to a living organism to produce a desired, usually beneficial, effect. This includes therapeutic agents in all the major therapeutic areas including, but not limited to: anti-infectives, such as antibiotics and antiviral agents; analgesics, including fentanyl, sufentanil, buprenorphine and analgesic combinations; anesthetics; anorexics; antiarthritics; antiasthmatic agents; such as terbutaline; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antimotion sickness preparations, such as scopalomine and ondansetron; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics, including gastrointestinal and urinary; antocholinergics; sympathomimetrics; xanthine derivatives; cardiovascular preparations, including calcium channel blockers such as nifedipine; beta blockers; beta-agonists, such as dobutamine and ritodrine; antiarrythmics; antihypertensives, such as atenolol; ACE inhibitors, such as rinitidine; diuretics; vasodilators, including general, coronary, peripheral, and cerebral; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones, such as parathyroid hormone; hypnotics; immunosuppressants; muscle relaxants; parasympatholytics; parasympathomimetrics; prostaglandins; proteins; peptides; psychostimulants; sedatives; and tranquilizers.
The invention is also useful in the controlled delivery of peptides, polypeptides, proteins and other macromolecules. These macromolecular substances typically have a molecular weight of at least 300 Daltons, and more typically have a molecular weight of 300-40,000 Daltons. Specific examples of peptides and proteins in this size range include, without limitation, the following: LHRH; LHRH analogs, such as buserelin, gonadorelin, napharelin and leuprolide; insulin; insulotropin; heparin; calcitonin; octreotide; endorphin; TRH; NT-36 (chemical name is N.dbd.[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide); liprecin; pituitary hormones, such as HGH, HMG, HCG and desmopressin acetate; follicle luteoids; aANF; growth factors, such as growth factor releasing factor (GFRF or GHRH); bMSH; somatostatin; bradykinin; somatotropin; platelet-derived growth factor; asparaginase; bleomycin sulfate; chymopapain; cholecystokinin; chorionic gonadotropin; corticotropin (ACTH); erythropoietin; epoprostenol (platelet aggregation inhibitor); glucagon; hirulog; hyaluronidase; interferon; interleukin-1; interleukin-2; menotropins (urofollitropin (FSH) and LH); oxytocin; streptokinase; tissue plasminogen activator; vasopressin; desmopressin; ACTH analogs; ANP; ANP clearance inhibitors; angiotensin II antagonists; antidiuretic hormone agonists; antidiuretic hormone antagonists; bradykinin antagonists; CD-4; ceredase; CSFs; enkephalins; FAB fragments; IgE peptide suppressors; IGF-1; neurotrophic factors; colony stimulating factors; parathyroid hormone and agonists; parathyroid hormone antagonists; prostaglandin antagonists; pentigetide; protein C; protein S; renin inhibitors; thymosin alpha-1; thrombolytics; TNF; vaccines; vasopressin antagonist analogs; alpha-1 anti-trypsin (recombinant); and TGF-beta.
Existing iontophoresis devices generally require a reservoir or source of the agent, or a precursor of such agent, that is to be iontophoretically delivered or introduced into the body. Examples of such reservoirs or sources of, preferably ionized or ionizable, agent include a pouch as described in U.S. Pat. No. 4,250,878 issued to Jacobsen, or a pre-formed gel body as disclosed in U.S. Pat. No. 4,383,529 issued to Webster. Such reservoirs are electrically connected to the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired species.
Recently, a number of U.S. Patents have issued in the iontophoresis field, indicating a continuing interest in this mode of drug delivery. For example, Vernon et al U.S. Pat. No. 3,991,755, Jacobsen et al U.S. Pat. No. 4,141,359, Wilson U.S. Pat. No. 4,398,545, and Jacobsen U.S. Pat. No. 4,250,878 disclose examples of iontophoretic devices and some applications thereof.
The Dietz U.S. Pat. No. 3,215,139 discloses an iontophoretic delivery device for delivering fluoride to teeth. FIG. 12 of this patent shows a power supply consisting of batteries 102 and 104, either one of which is connectable into the circuit via switch 78. However, no provision is made for connecting both batteries simultaneously into the circuit.
The Sibalis U.S. Pat. No. 4,708,716 uses simply a series connection of a plurality of batteries as its power supply.
The Sibalis published European Patent application No. 88108314.1 uses a pair of batteries, either one of which is connectable into the circuit. However, like the Dietz patent, no provision is made to connect both batteries into the circuit at once.
As the above references illustrate, iontophoretic delivery devices for administering a wide range of drugs have become far more compact and inexpensive than the bulky, immobilizing apparatuses of the past. The advent of inexpensive miniaturized electronic circuitry and compact, high-energy batteries has meant that the entire device can be unobtrusively worn on the skin of the patient, who remains fully ambulatory and able to perform all normal activities. At the same time, the development of suitable chemistry and materials has made practical the iontophoretic administration of a much wider range of beneficial agents than was heretofore possible.
Nevertheless, some limitations still remain, restricting the wider application of this valuable technique. One such limitation is the cost of the iontophoretic device. In particular, the miniature batteries needed to power the iontophoretic device can comprise the most expensive element in the system. If it were possible to achieve a meaningful reduction in the cost of these batteries, iontophoresis could achieve a still further penetration of the highly competitive drug-delivery market.
The problem of reducing the cost of the batteries is complicated by the fact that the power-supply requirements are not constant during the utilization cycle of the iontophoretic device: When iontophoretic administration is begun, the patient's initial skin resistance is relatively high, requiring the supply to produce relatively high voltage. However, once iontophoretic delivery is established, the skin resistance drops, such that the voltage requirement may be less than one half the voltage required at the start.
Although various regulator circuits can be used to accommodate the varying voltage requirement, they reduce the efficiency of the apparatus and typically require that more battery capacity be provided, resulting in increased battery costs. A more cost-effective solution which makes optimal use of the batteries without wasting their energy in a regulator circuit is needed.